Achievement of CR and nCR Before and After First High-Dose Therapy Followed by Autologous Stem Cell Transplantation
Is a Major Marker for Long-Term Survival in Multiple Myeloma Patients
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Hartmut Goldschmidt1,2, Gerlinde Egerer1, Ute Hegenbart1, Markus Munder1, Thomas Hielscher3, Christiane Heiß1,3, Uta Bertsch1, Jens Hillengaß1, Jana Schlenzka ,
Marc-Steffen Raab1, Dirk Hose1,2, Michael Hundemer1, Kai Neben1 and Anthony D. Ho1
(1)Department of Internal Medicine V, University of Heidelberg, Germany; (2) National Center for Tumor Diseases (NCT), Heidelberg, Germany;
(3) Division of Biostatistics, German Cancer Research Center Heidelberg, Germany
Introduction
Table 3: Patient Characteristics at Diagnosis
first ASCT, achieving CR or nCR remained a significant prognostic factor (PFS after
ASCT: HR=0.66 [0.54;0.80], p<0.001; OS after ASCT: HR=0.65 [0.51;0.83],
At Diagnosis
p=0.001). Figure 1 shows the Kaplan-Meier-Plot for the CR/nCR vs. other groups for
SD stage I
129 [13.0]
PFS and OS since first ASCT, respectively.
In Multiple Myeloma (MM), the CR rate was lower than 10% with conventional
II
107 [10.8]
chemotherapy and the majority of trials failed to show a significant influence of the
III (n [%])
756 [76.2]
degree of response on survival. As a result of the introduction of high-dose therapy
(HDT) followed by autologous stem-cell transplantation (ASCT) the rate of CR could
MM Isotype IgA
207[20.8]
be incr
inc eased
eas
to 30-50%. The prognost
pro
i
gnost c impact of CR or VGPR
VGP
achieve
achi
m
eve ent was
IgG
573 [57.6]
6]
considered in many trials (s. Table 1).
IgD
17 [1.7
BJ
159 [16.0]
Table 1: Association between Maximal Response and Overall Survival (OS) in
asecr./hypsecr.
23 [2.3]
Patients with MM Treated with ASCT
other (n [%])
8 [0.8]
Maximal Response
Age (median [range])
57.8 [25.3, 75.7]
Sex (male / female) (n [%])
579 [58.2] / 415 [41.8]
Prospective Study
Comparison
P Value
IFM90
CR/VGPR vs. PR vs. other
<0.001
91 patients received an allogeneic SCT, 30 of these before first progression after
MRC VII
CR vs. PR vs. MR
<0.001
ASCT. These were censored for PFS at time of allogeneic SCT. Maintenance therapy
(interferon n=332, thalidomide n=203, bortezomib n=48 or others n=13) was
TT1
CR vs. PR
0.25
administered in 596 patients.
TT2
CR vs. PR/NR
<0.05
Table 4: Induction Treatment and No. of ASCT
IFM94-02
Maximal Response
<0.001
IFM99C
CR/VGPR vs. PR
<0.001
Treatment
Figure 1: Kaplan -Meier-Plots for PFS and OS
NMSG 5/94
CR vs. PR/NR
0.4
Induction regime
In addition, we analyzed the effect of duration of response compared to response
Thalidomide-based
129 [13.0]
Bologna
VGPR vs. other
0.002
achievement per se. Patients who sustained their remission (overall response = PR
Lenalidomide-based
1 [0.1]
and better) at 3 yrs after first ASCT had a favourable prognosis with respect to OS
GMA
CR/MRD vs. other
0.2
Bortezomib-based
75 [7.5]
compared to patients losing remission. Figure 2 (left) shows the impact of sustained
Meta-Analysis
CR/VGPR vs. PR vs. other
<0.001
Only Chemotherapy (VAD etc.)
758 [76.3]
nCR/CR. As expected, the duration of no nCR/CR is also a prognostic factor (s.
Other
Figure 2 right).
(n [%])
31 [3.1]
Adapted from Van de Velde H et al. Complete response correlates with long-
term survival and progression-free survival in high-dose therapy in multiple
No. of ASCT
myelom
y
a. Haematologica 2007; 92:1399-1406
1
460 [46.3]
2
437 [44.0]
Patient Characteristics and Methods
3 (n [%])
97 [9.8]
Allogeneic SCT (yes/no [%])
91 [9.2] / 903 [90.8]
To analyse the impact of CR, near CR (nCR) and very good partial response (VGPR)
Overall survival and progression-free survival were calculated from the time of first
before and after first HDT followed by ASCT on overall survival (OS) and
ASCT. Log-rank test, univariate and multivariate Cox PH regression as well as
prog
pgression-free survival (PFS),
(), we evaluated 994 pat
p ients with MM who underwent
landmark analyses
y
were utilized to assess the prog
pgnostic impact of response.
an ASCT in frontline treatment at our centre. The transplantations were performed
Figure 2: Duration of Response
between June 1992 and February 2009 giving a minimum follow up of 5 months after
ASCT. The median follow-up after first ASCT was 5.8 years.
Results
Conclusions
Table 2: Risk Factors at Start of Induction and at Time of ASCT
In our single-center cohort achieving CR or nCR before and after first HDT is highly
At Start of Induction
At Time of ASCT
The median OS time was 5.7 years and the median PFS was 2.2 years Achieving CR
prognostic for PFS and OS in MM. Sustained duration of response is also associated
or nCR is a highly significant prognostic factor for PFS and OS before (p<0.001 and
Beta2MG [mg/l]
with an improved prognosis (3 years landmark analysis). At our centre we
2.8 [0.2, 68.8]
2.2 [0.7, 97.0]
p=0 01
. , respectiv
resp
e
ectiv ly)
ly and after first HDT (bot
(bo h
t p<0 001
.
; Figure 1) Th
.
e group
grou includi
incl
ng
udi
recomm d
en that patientsnot achi i
ev ng at lt
least an nCR hl
shou d
ld be tt
treated
it
w h
it a
(median [range])
VGPR showed superior outcome when assessed after HDT, driven by the effect of
second cycle of HDT.
Albumin [g/l]
CR/nCR. When adjusting for the effect of age, beta-2 microglobulin before ASCT,
39.4 [18.0, 58.0]
40.1 [14.0, 59.0]
(median [range])
albumin before ASCT, new drugs before ASCT (thalidomide and bortezomib; yes/no),
The Myeloma Center Heidelberg is supported by the "Dietmar-Hopp-Foundation". The
second ASCT within 9 months (yes/no), maintenance therapy (yes/no), and date of
scientific data base "MySam" is supported by unrestricted grants from Celgene,
ISS stage I / II / III (%)
49.1 / 30.2 / 20.7
71.3 / 21.1 / 7.7
Mundipharma, Novartis and Ortho Biotech.

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